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Muscle Growth and Regeneration

Normal skeletal muscle has a remarkable ability to grow following stimulation or regenerate following injury.  However, in many disease states, skeletal muscle does not regenerate from injury but progresses down a nonproductive path of fibrosis and fatty replacement.  The goal of my lab is to determine how to best influence diseased muscle to successfully regenerate.  

Hypotheses:  Skeletal muscle harbors its own adult progenitor cells, called satellite cells.  Satellite cells, as well as other poorly characterized mesenchymal stem cells are in a quiescent state until activated to proliferate and differentiate into new muscle.  Some of the factors that control satellite cell activation are known including IGF-1, myostatin, HGF and nerve impulses.  We believe that these and other factors can similarly dictate the transdifferentiation of muscle progenitor cells to cells constituting fibrosis.  Current questions that my lab is addressing include 1) What are the defining characteristics of muscle progenitor cells? 2) How do the various factors interact to control regeneration? 3) Can regeneration be enhanced with pharmacologic agents that modulate the signal transduction pathways of these growth factors?  4) What are the rudimentary molecular signatures of muscle regeneration versus disease?

Tools:  We are fortunate to have a wealth of tools at our disposable to address these questions including several mouse models of acute muscle injury and chronic muscle disease (muscular dystrophies) as well as mouse models that allow lineage tracing of mesenchymal cells, and various hypermuscular mice from over or underexpression of growth factors.  Human muscle biopsy samples and human cell lines also allow us to ask questions specific to human disease.

Techniques:   Muscle (compared to brain) is a relatively easy organ to study.  On a gross level, its function can be measured easily in terms of endurance and force.  It can be biopsied from living humans and transgenic animals and evaluated by histological and molecular methods.  It will grow, fuse and contract in a dish.  With these techniques and tools, we hope to better understand the factors governing muscle regeneration and harness them for development of novel therapeutics for the many human conditions associated with muscle weakness and wasting.